Inhibition of I‐Ad‐, but not Db‐restricted peptide‐induced thymic apoptosis by glucocorticoid receptor antagonist RU486 in T cell receptor transgenic mice

Thymocytes differentiate by positive and negative selection of immature CD4+ CD8+ T cells. Negative selection occurs by default or by high‐affinity recognition of peptides bound to proteins encoded by the major histocompatibility complex (MHC). MHC class I molecules are expressed on many different cell types, although at different levels, whereas MHC class II molecules are selectively expressed on thymic epithelial cells (TEC) and dendritic cells (DC). We investigated the role of the glucocorticoid receptor (GR) in thymic negative selection using the receptor antagonist RU486. Glucocorticoids (GC) are known to be potent inducers of apoptosis in CD4+ CD8+ thymocytes, and we have earlier shown that anti‐CD3‐induced thymic apoptosis can be blocked by RU486 in vivo. We now show that anti‐CD3 induces thymic apoptosis in mice that have been adrenalectomized (ADX), and that RU486 inhibits anti‐CD3 antibody‐mediated thymocyte killing in newborn thymic organ cultures. Thymocyte apoptosis induced by ovalbumin peptide OVA323–339 treatment of mice transgenic for the DO11.10T cell receptor (TCR), which recognizes this peptide in the context of I‐Ad, was found to be inhibited by RU486. These mice responded to peptide treatment by an extensive activation of the peripheral immune system, which became lethal in 60% of the mice when accompanied by simultaneous RU486 treatment. In contrast, RU486 had no effect on thymic apoptosis induced by the influenza A nucleoprotein NP366–374 peptide, recognized in context of Db, in F5 TCR transgenic mice. We interpret the results to demonstrate that different deletion systems operate in the thymus. We propose that endogenous GC may be important for negative selection by default and by high‐affinity recognition of endogenous MHC‐presented peptides on TEC.